Clinical depression (also called major-depressive disorder or unipolar depression) is a common psychiatric disorder, characterized by a persistent lowering of mood, loss of interest in usual activities and diminished ability to experience pleasure.
While the term “depression” is commonly used to describe a temporary decreased mood when one “feels blue,” clinical depression is a serious illness that involves the body, mood, and thoughts and cannot simply be willed or wished away. It is often a disabling disease that affects a person's work, family and school life, sleeping and eating habits, general health and ability to enjoy life. The course of clinical depression varies widely: depression can be a once in a life-time event or have multiple recurrences, it can appear either gradually or suddenly, and either last for few months or be a life-long disorder. Having depression is a major risk factor for suicide; in addition, people with depression suffer from higher mortality from other causes. Clinical depression is usually treated by psychotherapy, antidepressants, or a combination of the two.
Neuropathy is a disease of the peripheral nerve or nerves. The four major forms of nerve damage are polyneuropathy, autonomic neuropathy, mononeuropathy, and mononeuritis multiplex. A more common form is peripheral polyneuropathy, which mainly affects the feet and legs. There are other less common forms of neuropathy, for example enteric neuropathy.
Aside from diabetes (i.e., diabetic neuropathy), the common causes of neuropathy are herpes zoster infection, HIV-AIDS, toxins, alcoholism, chronic trauma (such as repetitive motion disorders) or acute trauma (including surgery), neurotoxicity and autoimmune conditions such as celiac disease. Neuropathic pain is common in cancer as a direct result of the cancer on peripheral nerves (e.g., compression by a tumor), as a side effect of many chemotherapy drugs, and as a result of electrical injury. In many cases the neuropathy is “idiopathic,” meaning no cause is found.
Neuropathic pain is usually perceived as a steady burning and/or “pins and needles” and/or “electric shock” sensations and/or tickling. The difference is due to the fact that “ordinary” pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool) sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive.
Neuropathic pain and depression may be difficult to treat. Antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, major depressive disorder (MDD), neuropathic pain, nocturnal enuresis, and ADHD, but they have also been used successfully for headaches (including migraine headache), anxiety, insomnia, smoking cessation, bulimia nervosa, irritable bowel syndrome, narcolepsy, pathological crying or laughing, persistent hiccups, interstitial cystitis, and ciguatera poisoning, stress urinary incontinence, fibromyalgia, and as an adjunct in schizophrenia.
It is generally thought that many antidepressants work by inhibiting the re-uptake of the neurotransmitters; norepinephrine, dopamine, and/or serotonin by nerve cells. Antidepressants may also possess an affinity for muscarinic and histamine H1 receptors to varying degrees. Although norepinephrine and dopamine are generally considered stimulatory neurotransmitters, many antidepressants also increase the effects of H1 histamine, and thus may have sedative effects.
The utility of antidepressants has been limited by potential adverse effects on the central nervous system such as bad dreams, drowsiness, blurred vision, decreased gastro-intestinal mobility and secretion, hyperthermia, and dry mouth. As a consequence, pharmacotherapy with antidepressants would be improved if these and/or other side effects associated with their use could be decreased. Thus, there is a large unmet need for developing novel compounds with such properties.
The present invention seeks to address these and other needs in the art.